PDF - Glaucoma Today

Transcription

Supplement to
July/August 2015
Glaucoma Disease
Diagnosis and
Management Update
A review of the latest developments in the field.
Supported via advertising by Alcon and Reichert
Glaucoma Disease Diagnosis and Management Update
Glaucoma Disease Diagnosis
and Management Update
BY STEVEN D. VOLD, MD
Both the diagnosis and management of glaucoma continue to evolve at a rapid rate. Advancements in
diagnostic testing allow clinicians to both diagnose glaucoma at earlier stages as well as more accurately
detect glaucoma progression. Our understanding of how potential glaucoma risk factors, such as IOP
fluctuation and corneal hysteresis actually impact disease progression, is also coming into clearer view.
Intraocular IOP sensors and corneal biomechanical measurements are quickly becoming significant additions to the glaucoma diagnostic technology library.
The glaucoma treatment paradigm has also been impacted by a variety of advances in medical therapy as well.
These include the availability of additional fixed-combination agents, preservative-free medication alternatives,
improved laser technologies, and more minimally invasive glaucoma procedures. The use of generic medications
now plays a much more prominent role in medical glaucoma treatment than in the past, as well. How generic medications impact glaucoma patient care is yet to be fully elucidated. Glaucoma medication side effect profiles and
increasing medication costs also influence clinical decision-making, patient medical compliance, and ultimately glaucoma outcomes.
In this supplement, several key leaders in our field share their impressions as to where we are now as well as future
directions in glaucomatous disease diagnosis and management. n
CONTENTS
The Role of Visual Field in Assessing Glaucoma. . . . . . . . . . . . . . . . . . . . . . 5
By Steven R. Sarkisian Jr, MD
The Role of Fixed-Combination Agents
in Management of Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
By Tony Realini, MD, MPH
IOP Fluctuation and Risk of Glaucoma:
Is There a Link? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
By Malik Y. Kahook, MD
The Knowns and Unknowns
of Generic Medications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
By Nathan M. Radcliffe, MD
Side Effect Profiles of Glaucoma Drug Classes. . . . . . . . . . . . . . . . . . . . . . . 14
By Robert J. Noecker, MD, MBA
2 SUPPLEMENT TO GLAUCOMA TODAY JULY/AUGUST 2015
ADD SIMBRINZA® Suspension to a PGA for Even Lower IOP1*
INDICATIONS AND USAGE
SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension)
1%/0.2% is a fixed combination indicated in the reduction of elevated
intraocular pressure (IOP) in patients with open-angle glaucoma or
ocular hypertension.
Dosage and Administration
The recommended dose is one drop of SIMBRINZA® Suspension in the
affected eye(s) three times daily. Shake well before use. SIMBRINZA®
Suspension may be used concomitantly with other topical ophthalmic drug
products to lower intraocular pressure. If more than one topical ophthalmic
drug is being used, the drugs should be administered at least five (5)
minutes apart.
IMPORTANT SAFETY INFORMATION
Contraindications
SIMBRINZA® Suspension is contraindicated in patients who are hypersensitive
to any component of this product and neonates and infants under the age of
2 years.
Warnings and Precautions
Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide,
and although administered topically, is absorbed systemically. Sulfonamide
attributable adverse reactions may occur. Fatalities have occurred due
to severe reactions to sulfonamides. Sensitization may recur when a
sulfonamide is readministered irrespective of the route of administration.
If signs of serious reactions or hypersensitivity occur, discontinue the use
of this preparation.
Corneal Endothelium—There is an increased potential for developing
corneal edema in patients with low endothelial cell counts.
Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA®
Suspension has not been specifically studied in these patients and is
not recommended.
Contact Lens Wear—The preservative in SIMBRINZA® Suspension,
benzalkonium chloride, may be absorbed by soft contact lenses. Contact
lenses should be removed during instillation of SIMBRINZA® Suspension
but may be reinserted 15 minutes after instillation.
Severe Cardiovascular Disease—Brimonidine tartrate, a component of
SIMBRINZA® Suspension, had a less than 5% mean decrease in blood
pressure 2 hours after dosing in clinical studies; caution should be
exercised in treating patients with severe cardiovascular disease.
Adverse Reactions
SIMBRINZA® Suspension
In two clinical trials of 3 months’ duration with SIMBRINZA® Suspension,
the most frequent reactions associated with its use occurring in approximately
3-5% of patients in descending order of incidence included: blurred vision,
eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Adverse
reaction rates with SIMBRINZA® Suspension were comparable to those of
the individual components. Treatment discontinuation, mainly due to adverse
reactions, was reported in 11% of SIMBRINZA® Suspension patients.
Prescribe SIMBRINZA® Suspension as adjunctive
therapy to a PGA for appropriate patients
SIMBRINZA® Suspension should be taken at least five
(5) minutes apart from other topical ophthalmic drugs
Learn more at myalcon.com/simbrinza
For additional information about SIMBRINZA® Suspension, please see
Brief Summary of full Prescribing Information on adjacent page.
Reference: 1. Data on file, 2014.
© 2015 Novartis 3/15 SMB15017JAD
Up to
7.1 mm Hg
additional IOP
reduction from
baseline when
added to a PGA1
5.6† mm Hg additional mean diurnal
IOP lowering observed from baseline
when added to a
PGA1
Treatment Arm
PGA + SIMBRINZA
Suspension (N=83)
®
PGA + Vehicle
(N=92)
Baseline§
Week 6
Baseline§
Week 6
IOP Time Points (mm Hg)1‡
8 am
10 am
3 pm
24.5
22.9
21.7
19.4
15.8
17.2
24.3
22.6
21.3
21.5
20.3
20.0
5 pm
21.6
15.6
21.2
20.1
Least squares means at each Week 6 time point. Treatment differences (mm Hg) and P-values at
Week 6 time points between treatment groups were: -2.14, P=0.0002; -4.56, P<0.0001; -2.84,
P<0.0001; -4.42, P<0.0001.
§
Baseline (PGA Monotherapy).
‡
Mean Diurnal IOP (mm Hg)1||
Treatment Arm
PGA + SIMBRINZA® Suspension (N=83)
PGA + Vehicle (N=92)
Baseline¶
Week 6
Baseline¶
Week 6
22.7
17.1
22.4
20.5
Treatment difference (mm Hg) and P-value at Week 6 was -3.4, P<0.0001.
Baseline (PGA Monotherapy).
||
¶
Study Design: A prospective, randomized, multicenter, double-blind, parallel-group
study of 189 patients with open-angle glaucoma and/or ocular hypertension receiving
treatment with a PGA. PGA treatment consisted of either travoprost, latanoprost,
or bimatoprost. Patients in the study were randomized to adjunctive treatment with
SIMBRINZA® Suspension (N=88) or vehicle (N=94). The primary efficacy endpoint was
mean diurnal IOP (IOP averaged over all daily time points) at Week 6 between treatment
groups. Key secondary endpoints included IOP at Week 6 for each daily time point
(8 am, 10 am, 3 pm, and 5 pm) and mean diurnal IOP change from baseline to Week 6
between treatment groups.1
*PGA study-group treatment consisted of either travoprost, latanoprost, or bimatoprost.
†
Treatment difference (mm Hg) and P-value at Week 6 was -3.7, P<0.0001.
BRIEF SUMMARY OF PRESCRIBING INFORMATION
INDICATIONS AND USAGE
SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic
suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase
inhibitor and an alpha 2 adrenergic receptor agonist indicated for the
reduction of elevated intraocular pressure (IOP) in patients with openangle glaucoma or ocular hypertension.
DOSAGE AND ADMINISTRATION
The recommended dose is one drop of SIMBRINZA® Suspension in the
affected eye(s) three times daily. Shake well before use. SIMBRINZA®
Suspension may be used concomitantly with other topical ophthalmic
drug products to lower intraocular pressure.
If more than one topical ophthalmic drug is being used, the drugs
should be administered at least five (5) minutes apart.
DOSAGE FORMS AND STRENGTHS
Suspension containing 10 mg/mL brinzolamide and 2 mg/mL
brimonidine tartrate.
CONTRAINDICATIONS
Hypersensitivity - SIMBRINZA® Suspension is contraindicated in
patients who are hypersensitive to any component of this product.
Neonates and Infants (under the age of 2 years) - SIMBRINZA®
Suspension is contraindicated in neonates and infants (under the age
of 2 years) see Use in Specific Populations
WARNINGS AND PRECAUTIONS
Sulfonamide Hypersensitivity Reactions - SIMBRINZA® Suspension
contains brinzolamide, a sulfonamide, and although administered
topically is absorbed systemically. Therefore, the same types of
adverse reactions that are attributable to sulfonamides may occur
with topical administration of SIMBRINZA® Suspension. Fatalities have
occurred due to severe reactions to sulfonamides including StevensJohnson syndrome, toxic epidermal necrolysis, fulminant hepatic
necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.
Sensitization may recur when a sulfonamide is re-administered
irrespective of the route of administration. If signs of serious reactions
or hypersensitivity occur, discontinue the use of this preparation [see
Patient Counseling Information]
Corneal Endothelium - Carbonic anhydrase activity has been
observed in both the cytoplasm and around the plasma membranes of
the corneal endothelium. There is an increased potential for developing
corneal edema in patients with low endothelial cell counts. Caution
should be used when prescribing SIMBRINZA® Suspension to this
group of patients.
Severe Renal Impairment - SIMBRINZA® Suspension has not
been specifically studied in patients with severe renal impairment (CrCl
< 30 mL/min). Since brinzolamide and its metabolite are excreted
predominantly by the kidney, SIMBRINZA® Suspension is
not recommended in such patients.
Acute Angle-Closure Glaucoma - The management of patients with
acute angle-closure glaucoma requires therapeutic interventions in
addition to ocular hypotensive agents. SIMBRINZA® Suspension has
not been studied in patients with acute angle-closure glaucoma.
reported in 5 to 10% of patients were blurred vision and bitter, sour or
unusual taste. Adverse reactions occurring in 1 to 5% of patients were
blepharitis, dermatitis, dry eye, foreign body sensation, headache,
hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular
pain, ocular pruritus and rhinitis.
The following adverse reactions were reported at an incidence below
1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea,
diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue,
hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin
crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria.
Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate
0.2%, adverse reactions occurring in approximately 10 to 30% of the
subjects, in descending order of incidence, included oral dryness,
ocular hyperemia, burning and stinging, headache, blurring, foreign
body sensation, fatigue/drowsiness, conjunctival follicles, ocular
allergic reactions, and ocular pruritus.
Reactions occurring in approximately 3 to 9% of the subjects, in
descending order included corneal staining/erosion, photophobia,
eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper
respiratory symptoms, eyelid edema, conjunctival edema, dizziness,
blepharitis, ocular irritation, gastrointestinal symptoms, asthenia,
conjunctival blanching, abnormal vision and muscular pain.
The following adverse reactions were reported in less than 3% of
the patients: lid crusting, conjunctival hemorrhage, abnormal taste,
insomnia, conjunctival discharge, depression, hypertension, anxiety,
palpitations/arrhythmias, nasal dryness and syncope.
Postmarketing Experience - The following reactions have been
identified during postmarketing use of brimonidine tartrate ophthalmic
solutions in clinical practice. Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot
be made. The reactions, which have been chosen for inclusion
due to either their seriousness, frequency of reporting, possible
causal connection to brimonidine tartrate ophthalmic solutions, or a
combination of these factors, include: bradycardia, hypersensitivity,
iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions
(including erythema, eyelid pruritus, rash, and vasodilation), and
tachycardia.
Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia,
lethargy, pallor, respiratory depression, and somnolence have been
reported in infants receiving brimonidine tartrate ophthalmic solutions
[see Contraindications].
DRUG INTERACTIONS
Oral Carbonic Anhydrase Inhibitors - There is a potential for an
additive effect on the known systemic effects of carbonic anhydrase
inhibition in patients receiving an oral carbonic anhydrase inhibitor
and brinzolamide ophthalmic suspension 1%, a component of
SIMBRINZA® Suspension. The concomitant administration of
SIMBRINZA® Suspension and oral carbonic anhydrase inhibitors is not
recommended.
Contact Lens Wear - The preservative in SIMBRINZA® Suspension,
benzalkonium chloride, may be absorbed by soft contact lenses.
Contact lenses should be removed during instillation of SIMBRINZA®
Suspension but may be reinserted 15 minutes after instillation [see
Patient Counseling Information].
High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors
may produce acid-base and electrolyte alterations. These alterations
were not reported in the clinical trials with brinzolamide ophthalmic
suspension 1%. However, in patients treated with oral carbonic
anhydrase inhibitors, rare instances of acid-base alterations have
occurred with high-dose salicylate therapy. Therefore, the potential
for such drug interactions should be considered in patients receiving
SIMBRINZA® Suspension.
Severe Cardiovascular Disease - Brimonidine tartrate, a component
of SIMBRINZA® Suspension, has a less than 5% mean decrease in
blood pressure 2 hours after dosing in clinical studies; caution should
be exercised in treating patients with severe cardiovascular disease.
CNS Depressants - Although specific drug interaction studies have
not been conducted with SIMBRINZA® Suspension, the possibility of an
additive or potentiating effect with CNS depressants (alcohol, opiates,
barbiturates, sedatives, or anesthetics) should be considered.
Severe Hepatic Impairment - Because brimonidine tartrate, a
component of SIMBRINZA® Suspension, has not been studied in
patients with hepatic impairment, caution should be exercised in such
patients.
Antihypertensives/Cardiac Glycosides - Because brimonidine
tartrate, a component of SIMBRINZA® Suspension, may reduce blood
pressure, caution in using drugs such as antihypertensives and/or
cardiac glycosides with SIMBRINZA® Suspension is advised.
Potentiation of Vascular Insufficiency - Brimonidine tartrate, a
component of SIMBRINZA® Suspension, may potentiate syndromes
associated with vascular insufficiency. SIMBRINZA® Suspension should
be used with caution in patients with depression, cerebral or coronary
insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or
thromboangiitis obliterans.
Tricyclic Antidepressants - Tricyclic antidepressants have been
reported to blunt the hypotensive effect of systemic clonidine. It is not
known whether the concurrent use of these agents with SIMBRINZA®
Suspension in humans can lead to resulting interference with the
IOP lowering effect. Caution is advised in patients taking tricyclic
antidepressants which can affect the metabolism and uptake of
circulating amines.
Contamination of Topical Ophthalmic Products After Use - There
have been reports of bacterial keratitis associated with the use
of multiple-dose containers of topical ophthalmic products. These
containers have been inadvertently contaminated by patients who, in
most cases, had a concurrent corneal disease or a disruption of the
ocular epithelial surface [see Patient Counseling Information].
ADVERSE REACTIONS
Clinical Studies Experience - Because clinical studies are conducted
under widely varying conditions, adverse reaction rates observed in
the clinical studies of a drug cannot be directly compared to the rates
in the clinical studies of another drug and may not reflect the rates
observed in practice.
SIMBRINZA® Suspension - In two clinical trials of 3 months duration
435 patients were treated with SIMBRINZA® Suspension, and 915
were treated with the two individual components. The most frequently
reported adverse reactions in patients treated with SIMBRINZA®
Suspension occurring in approximately 3 to 5% of patients in
descending order of incidence were blurred vision, eye irritation,
dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse
reactions reported with the individual components were comparable.
Treatment discontinuation, mainly due to adverse reactions, was
reported in 11% of SIMBRINZA® Suspension patients.
Other adverse reactions that have been reported with the individual
components during clinical trials are listed below.
Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic
suspension 1%, the most frequently reported adverse reactions
Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO)
inhibitors may theoretically interfere with the metabolism of
brimonidine tartrate and potentially result in an increased systemic
side-effect such as hypotension. Caution is advised in patients taking
MAO inhibitors which can affect the metabolism and uptake of
circulating amines.
USE IN SPECIFIC POPULATIONS
Pregnancy - Pregnancy Category C: Developmental toxicity
studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/kg/
day (20, 60, and 120 times the recommended human ophthalmic dose)
produced maternal toxicity at 6 mg/kg/day and a significant increase
in the number of fetal variations, such as accessory skull bones,
which was only slightly higher than the historic value at 1 and 6 mg/
kg. In rats, statistically decreased body weights of fetuses from dams
receiving oral doses of 18 mg/kg/day (180 times the recommended
human ophthalmic dose) during gestation were proportional to the
reduced maternal weight gain, with no statistically significant effects
on organ or tissue development. Increases in unossified sternebrae,
reduced ossification of the skull, and unossified hyoid that occurred
at 6 and 18 mg/kg were not statistically significant. No treatmentrelated malformations were seen. Following oral administration of
14
C-brinzolamide to pregnant rats, radioactivity was found to cross the
placenta and was present in the fetal tissues and blood.
Developmental toxicity studies performed in rats with oral doses of
0.66 mg brimonidine base/kg revealed no evidence of harm to the
fetus. Dosing at this level resulted in a plasma drug concentration
approximately 100 times higher than that seen in humans at the
recommended human ophthalmic dose. In animal studies, brimonidine
crossed the placenta and entered into the fetal circulation to a limited
extent.
There are no adequate and well-controlled studies in pregnant women.
SIMBRINZA® Suspension should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers - In a study of brinzolamide in lactating rats,
decreases in body weight gain in offspring at an oral dose of 15 mg/
kg/day (150 times the recommended human ophthalmic dose) were
observed during lactation. No other effects were observed. However,
following oral administration of 14C-brinzolamide to lactating rats,
radioactivity was found in milk at concentrations below those in the
blood and plasma. In animal studies, brimonidine was excreted in
breast milk.
It is not known whether brinzolamide and brimonidine tartrate are
excreted in human milk following topical ocular administration.
Because many drugs are excreted in human milk and because
of the potential for serious adverse reactions in nursing infants
from SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic
suspension) 1%/0.2%, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use - The individual component, brinzolamide, has
been studied in pediatric glaucoma patients 4 weeks to 5 years
of age. The individual component, brimonidine tartrate, has been
studied in pediatric patients 2 to 7 years old. Somnolence (50-83%)
and decreased alertness was seen in patients 2 to 6 years old.
SIMBRINZA® Suspension is contraindicated in children under the age
of 2 years [see Contraindications].
Geriatric Use - No overall differences in safety or effectiveness have
been observed between elderly and adult patients.
OVERDOSAGE
Although no human data are available, electrolyte imbalance,
development of an acidotic state, and possible nervous system
effects may occur following an oral overdose of brinzolamide. Serum
electrolyte levels (particularly potassium) and blood pH levels should
be monitored.
Very limited information exists on accidental ingestion of brimonidine
in adults; the only adverse event reported to date has been
hypotension. Symptoms of brimonidine overdose have been reported
in neonates, infants, and children receiving brimonidine as part of
medical treatment of congenital glaucoma or by accidental oral
ingestion. Treatment of an oral overdose includes supportive and
symptomatic therapy; a patent airway should be maintained.
PATIENT COUNSELING INFORMATION
Sulfonamide Reactions - Advise patients that if serious or unusual
ocular or systemic reactions or signs of hypersensitivity occur, they
should discontinue the use of the product and consult their physician.
Temporary Blurred Vision - Vision may be temporarily blurred
following dosing with SIMBRINZA® Suspension. Care should be
exercised in operating machinery or driving a motor vehicle.
Effect on Ability to Drive and Use Machinery - As with other
drugs in this class, SIMBRINZA® Suspension may cause fatigue and/
or drowsiness in some patients. Caution patients who engage in
hazardous activities of the potential for a decrease in mental alertness.
Avoiding Contamination of the Product - Instruct patients that
ocular solutions, if handled improperly or if the tip of the dispensing
container contacts the eye or surrounding structures, can become
contaminated by common bacteria known to cause ocular infections.
Serious damage to the eye and subsequent loss of vision may
result from using contaminated solutions [see Warnings and
Precautions ]. Always replace the cap after using. If solution
changes color or becomes cloudy, do not use. Do not use the product
after the expiration date marked on the bottle.
Intercurrent Ocular Conditions - Advise patients that if they have
ocular surgery or develop an intercurrent ocular condition (e.g., trauma
or infection), they should immediately seek their physician’s advice
concerning the continued use of the present multidose container.
Concomitant Topical Ocular Therapy - If more than one topical
ophthalmic drug is being used, the drugs should be administered at
least five minutes apart.
Contact Lens Wear - The preservative in SIMBRINZA® Suspension,
benzalkonium chloride, may be absorbed by soft contact lenses.
Contact lenses should be removed during instillation of SIMBRINZA®
Suspension, but may be reinserted 15 minutes after instillation.
©2013 Novartis
U.S. Patent No:
6,316,441
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
1-800-757-9195
[email protected]
© 2015 Novartis 3/15
SMB15017JAD
The Role of Visual Field in
Assessing Glaucoma
Information gleaned from visual field testing is additive in assessing patients’ glaucoma and
risk for progression.
BY STEVEN R. SARKISIAN JR, MD
L
Photo courtesy of Shakeel Shareef, MD
ike most of the prognostic and diagnostic information we gather in the clinic to assess the status of a
glaucoma suspect or patient, visual field (VF) data
is best utilized in the context of all the data points collected. Properly understanding where a patient is on
the continuum of the glaucoma spectrum involves the
ocular and systemic history, optic nerve findings, results
of visual field testing and other imaging (if warranted), a
complete eye examination, and measurement of the IOP.
In truth, not one of these is necessarily more important
than another.
possible with our current technology.
I tell my patients that the automated VF machine is
measuring an island in a sea of darkness. The entire island
does not just sink into the sea all at once when the glaucoma winds blow, but rather it erodes slowly over time.
This is why glaucomatous damage sneaks up on people,
and, therefore, why regular VF testing can be helpful to
detect glaucoma progression before it becomes symptomatic if the glaucoma is diagnosed in a timely fashion.
TYPES OF VF TESTING
There are various forms of VF testing, some of which
ROLE OF VF TESTING
may be more appropriate for monitoring glaucoma than
The great hope in glaucoma is that we will be able to
others. Confrontation VF testing is part of the basic eye
predict exactly who will progress from ocular hypertenexamination and should be performed on all patients
sion to glaucoma, and when a patient develops glauon a regular basis. Frequency doubling perimetry (FDT)
coma, we will be able to know which patients require
is considered a screening test by most ophthalmolomore urgent follow up due to their risk of progression.
gists and has not been generally adopted by glaucoma
Sadly, however, that level of prognostic specificity is not
specialists as being the standard for following patients
with well-defined VF
defects over time.
However, as FDT
targets ganglion cells
in the magnocellular
pathway, the portion
of the ganglion cell
layer responsible for
transmitting information about flicker
and motion, this test
may in fact be predictive of early glaucomatous changes.1,2
Automated
perimetry, such
as the Humphrey
VF, is the generally
accepted method
Figure 1. A Humphrey 30-2 Swedish interactive thresholding algorithm standard visual field test of
of measuring the VF
the patient’s right and left eyes following her referral.
and monitoring for
JULY/AUGUST 2015 SUPPLEMENT TO GLAUCOMA TODAY 5
progression. Some patients are unable to fixate for the
duration of the Humphrey test or are otherwise unable
to complete the test, and so manual perimetry, such as
Goldman Perimetry, may be required.
The most typical pattern of VF loss in patients with
glaucoma is around the central 24° to 30° on standard
automated perimetry (SAP), which makes sense given
the loss of arcuate fibers of the retinal nerve fiber layer
in the inferior hemifield that is hallmark of early glaucomatous progression. However, SAP is not specific to
the involved ganglion subtypes of this region, and, thus,
patients quite typically experience optic nerve damage
prior to displaying visual field defect on SAP testing.
Given the lack of specificity in SAP, testing algorithms
have been devised to amplify changes indicative of early
glaucomatous progression—that is, testing that targets
the cells most typically damaged by early glaucomatous
changes. Notably, the Swedish Interactive Threshold
Algorithm (SITA) used on the Humphrey perimeter
maps the dimmest stimuli that will be detected 50% of
the time in 54 points on the macula in the 24-2 VF test
(and on 76 points in the 30-2 VF test) and determines
threshold values for each location in relation to nearby
points using a mathematical algorithm. This potentially
delivers a precise and repeatable pattern on the VF test
output. Such a testing algorithm can be combined with
short-wavelength automated perimetry (SWAP) in select
patients (ie, those who can fixate through the long duration of the test time and who do not have significant
nuclear sclerosis) to detect early ganglion cell loss changes, perhaps even before optic nerve damage occurs.
SWAP testing takes advantage of the koniocellular
pathway and has been shown to identify early glaucomatous changes.3,4 However, it is prone to test-retest variability and is limited by media opacities. Additionally, the
time required for fixation is long and intolerable to some
patients, although its incorporation in Humphrey 24-2
testing shortens the test time and lessens the variability
of outcomes.
INCORPORATING VF IN PRACTICE
With all of these various tests available, the question
becomes how to incorporate them into practice. And,
again, the answer is that it depends on the context. For
patients referred to my practice with a SITA Fast VF test
or a frequency doubling VF test, I will conduct a SITA
standard Humphrey VF. I rarely use the SITA Fast in my
practice, because it is not the best test to monitor progression over time. In reality, a SITA Standard HVF may
only take an extra couple of minutes compared to a SITA
Fast and if you perform a 24-2, rather than a 30-2, the
timing is often equivalent.
If the patient has preperimetric glaucoma, I may consider getting a SITA-SWAP protocol Humphrey VF to
detect for early loss if the optic nerve imaging shows early
nerve fiber layer thinning. However, the ability to conduct
the test will depend on the patient’s ability to fixate.
For patients presenting with low vision, it may be necessary to increase the target size; however, in my experience, most of these patients are able to perform the
Humphrey 10-2 test.
Recent studies tracking usage patterns of VF and other
imaging devices, namely OCT, have shown that VF testing has unfortunately fallen out of favor.5 It appears that
some physicians are relying on advanced imaging alone,
rather than both imaging and VF testing.
OCT on its own is not enough for the definitive diagnosis of glaucoma, although it can be crucial for monitoring over time. Imaging studies do play a significant
role in diagnosing glaucoma, yet they should not be
used in the absence of VF testing—the exception being
patients in whom the Humphrey VF is normal. In such
patients, it may be possible to repeat the Humphrey VF
every couple of years if the OCT continues to be stable.
Such cases may be rare, however, and I would truly only
consider this in my most reliable and compliant glaucoma suspects and patients with ocular hypertension who
have been stable for a reasonable period of time and
who show up to all of their appointments.
CONCLUSION
Humphrey VF changes are fundamentally useful in managing glaucoma. If a patient has a confirmed, repeatable
glaucoma-related VF defect that is progressing, this is a clear
indicator for more advanced treatment. Alternatively, if the
Humphrey VF is stable, it may be plausible to defer more
advanced treatment, even if the IOP is borderline.
Unfortunately, you cannot rely on VF alone, and you
must look at it in the context of the entire history and
examination. Yet, VF testing remains a crucial and central
component of composing a complete clinical picture of
the individual glaucoma patient. n
Steven R. Sarkisian Jr, MD, is the glaucoma
fellowship director at the Dean McGee Eye
Institute, and he is a clinical professor at the
University of Oklahoma College of Medicine in
Oklahoma City. He has no financial interests
related to this article. Dr. Sarkisian may be reached at
(405) 271-1093; [email protected].
1. Cioffi GA, Mansberger S, Spry P, et al. Frequency doubling perimetry and the detection of eye disease in the
community. Tr Am Ophth Soc. 2000;98:195-202.
2. Spry PGD, Johnson CA, McKendrick AM, et al. Variability components of standard automated perimetry and
frequency doubling technology perimetry. Invest Ophthalmol Vis Sci. 2001;42:1404-1410.
3. Johnson CA, Adams AJ, Casson EJ, et al. Progression of early glaucomatous visual field loss for blue-on-yellow
and standard white-on-white automated perimetry. Arch Ophthalmol. 1993;111:651-656.
4. Demirel S, Johnson CA. Incidence and prevalence of short wavelength automated perimetry deficits in ocular
hypertensive patients. Am J Ophthalmol. 2001;131:709-715.
5. Stein JD, Talwar N, Laverne AM, et al. Trends in use of ancillary glaucoma tests for patients with open-angle
glaucoma from 2001 to 2009. Ophthalmology. 2012;119(4):748-758.
The Role of Fixed-Combination
Agents in Management
of Glaucoma
Evolving treatment standards may include a more prominent role for combination agents as
adjuvant therapy.
BY TONY REALINI, MD, MPH
P
rostaglandin analogue (PGA) therapy is a firstline mainstay for treating patients with glaucoma.
However, some patients will require adjunctive
therapy to achieve the target IOP. A smaller subset
of patients may not tolerate prostaglandins and may
require a switch to a different class of medicines.
Fixed-combination agents are becoming a popular
choice for adjunctive therapy to PGAs or as alternative
therapy if PGA therapy is inappropriate, ineffective, or
poorly tolerated. There are three fixed-combinations
available in the United States: dorzolamide hydrochloride 2.0%/timolol 0.5% was approved by the US Food
and Drug Administration (FDA) almost 20 years ago;
brimonidine 0.2%/timolol 0.5% (Combigan, Allergan)
has been in use for about 10 years; and, more recently,
brinzolamide 1%/brimonidine 0.2% (Simbrinza, Alcon)
was approved by the FDA.
THE ROLES OF FIXED-COMBINATION
AGENTS
To gain regulatory approval, each of these products
went through rigorous phase 3 clinical trials as monotherapy. Each has demonstrated efficacy and safety that generally mirrors concomitant dosing with constituent agents.
However, each of these agents was approved after the
introduction of PGAs. Thus, despite data supporting their
first-line efficacy and safety, these fixed combinations have
been uncommonly used as first-line therapy for glaucoma.
Instead, they are typically used as adjunctive therapy.
Historically, clinicians have followed the adage: start low
and go slow. This axiom dictates that we should add one
drug at a time, so as to best assess the incremental additivity of efficacy and clearly attribute new safety issues to
the newly added single agent.
This paradigm is now in transition. The reality is that
adding a single agent—whether it is a β-blocker, a carbonic anhydrase inhibitor (CAI), or brimonidine—to a PGA
generally provides only 2 mm Hg to 4 mm Hg of addition-
Fixed-combination agents are
becoming a popular choice for
adjunctive therapy to PGAs or as
alternative therapy if PGA therapy
is inappropriate, ineffective, or
poorly tolerated.
—Tony Realini, MD, MPH
al IOP reduction, on average. It is true that some patients
will have greater IOP reductions than the average, but others will have even less. If PGA therapy provides IOP reduction to within 2 mm Hg to 4 mm Hg of the target IOP, a
single agent adjunct is an entirely reasonable strategy.
But if PGA therapy falls far short of achieving target
IOP, adding a single agent may not be the most effective
next step.
Fixed-Combinations as First Adjunct
For a patient in whom the IOP is inadequately controlled on PGA monotherapy, a fixed-combination may
be the appropriate first adjunct. A series of industrysponsored phase 4 clinical trials have demonstrated that,
when added to a PGA, the various fixed-combinations
provide an average of 5 to 8 mmHg of additional IOP
reduction. This exceeds the expected benefit of singleagent therapy and may provide adequate IOP control
using a two-bottle, three-drop regimen.
There are sound arguments against adding two
drugs at once. We cannot know for certain that a single
agent would not have been enough unless we try it.
Incrementally adding constituents is a reasonable alternative but requires several extra office visits. We run the
risk of exposing patients to the side effects of drugs they
may not need. We also cannot be certain which agent
may be responsible for any new side effects that appear
after adding a fixed-combination. However, we are well
familiar with the adverse event profiles of all the constituents and can usually infer the causative component
when a safety issue arises. Also, some fixed-combinations
are only available as branded products and are more
expensive than their generic constituents.
Ultimately, the decision to use a fixed-combination
as a first adjunct, versus stepwise addition of constituent agents, should be made on an individual patient
basis considering all of these issues. If the incremental
approach is used and the need for two adjuncts is established, strong consideration should be given to dosing
the two adjuncts as a fixed-combination, as there are
numerous important benefits of fixed-combination
therapy over concomitant dosing.
PROS AND CONS OF COMBINATION AGENTS
There are many advantages to fixed-combinations
over concurrent administration of constituent drugs and
some disadvantages that clinicians should be aware of
before incorporating them into practice.
Some studies support an improved rate of adherence with therapy when the fixed-combination is used.
Adherence decreases as the therapeutic regimen becomes
more complex,1-3 and fixed-combination agents can help
simplify a multi-bottle, multi-drop regimen.
Likewise, fixed-combinations may avoid problems associated with use of multiple drops, such as the potential washout effect if a second drop is instilled too soon after a first
drop.4 Also, patients may be more likely to regularly refill
the prescriptions when on a regimen that includes a fixedcombination.5 There are potential cost savings for patients
using fixed-combination agents, especially for those with
drug coverage (ie, one copayment versus two). However,
patients without insurance or those without prescription
drug coverage may realize cost savings from two concomitant generics versus a branded fixed-combination.
There are some downsides to using fixed-combination
agents that physicians should be aware of. Namely, it is not
possible to titrate the concentration, frequency, or timing
of dosage of the constituents in a fixed-combination. For
instance, some patients may need adjunctive β-blockers
once daily, but with dorzolamide/timolol or brimonidine/
timolol, double that dose is required if the fixed-combination is prescribed twice daily, as its label indicates.
SELECTING A FIXED-COMBINATION
Once the decision is made to add a fixed-combination
to the IOP-lowering regimen, the attributes of the various
fixed-combinations should drive the selection process. In
terms of efficacy, the three combinations available in the
Once the decision is made to add
a fixed-combination to the IOPlowering regimen, the attributes
of the various fixed-combinations
should drive the selection process.
—Tony Realini, MD, MPH
US are roughly comparable in efficacy when added to a
PGA—although there are relatively few studies to inform
us, so the characterization of their adjunctive efficacy and
safety profiles remains incomplete.
Cost is another matter. Some of these combinations
are now available in generic formulations while others remain branded products. If cost is a factor—as it is
for the uninsured, those without pharmacy benefits, or
those in the Medicare doughnut hole—generic options
may be the best choice.
Safety issues can also drive the selection process. Two
of the three combinations contain the β-blocker timolol. There is nothing inherently wrong with β-blockers.
Indeed, prior to the PGA era, β-blockers formed the
cornerstone of glaucoma therapy. However, of the many
glaucoma drugs available, β-blockers have the most
serious potential side effects and the most contraindications, of which symptomatic bradycardia, second-degree
AV block, and reactive airway disease head the list.
Theoretical contraindications, such as diabetes, depression, and erectile dysfunction, have not been established
in clinical study as potential safety issues, nor have they
been observed at clinically meaningful rates, even in studies of systemic β-blocker therapy.
In addition to the safety issues discussed above, the
use of β-blockers for IOP reduction may pose efficacy
issues as well. The frustrating truth is that, at least in
most US studies, β-blockers provide minimal additional
IOP reduction when added to PGAs. For this reason,
there are no fixed-combination agents containing both
a PGA and a β-blocker in the United States (there are
three such products available in ex-US markets).
Another issue is the use of systemic β-blockers.
Glaucoma patients are generally older and are usually taking several medications to control concomitant chronic
conditions. Use of oral β-blockers for control of systemic
hypertension is common in this population. In these
patients, topical β-blockers—and fixed-combinations
(Continued on page 11)
IOP Fluctuation and Risk of
Glaucoma: Is There a Link?
Autonomous IOP monitoring devices under development may improve our understanding of
this important question.
BY MALIK Y. KAHOOK, MD
T
he effect of IOP fluctuation on the risk of developing
glaucoma and/or glaucoma progression has been
studied for years. To this point, however, we do not
have definitive answers as to what defines a significant
fluctuation, whether it is in fact relevant to the disease
process, and, if it is, how we can adjust our interventions
to decrease the amplitude of IOP peak and trough.
IOP fluctuations are generally understood to occur
in the short-, intermediate-, and long-term. Short-term
fluctuations are those that occur during various activities
such as sitting or lying down, blinking, or other physical
activities. Intermediate-term fluctuations occur during
any given day (diurnal and nocturnal) and are the result
of the sum of various short-term fluctuations as well as
longer-term changes in the habitual position (ie, standing,
sitting, supine), along with inherent differences in aqueous production and outflow (ie, the circadian rhythm of
aqueous flow) that are present in all patients. Long-term
fluctuations are those that occur between visits and are
influenced by various factors, such as disease progression
(ie, deterioration in outflow facility with higher IOP) and
changes in therapy (ie, added medications leading to lower
average IOP) among other factors. What is more difficult
to answer is the actual influence of all of these fluctuations
on disease presence and progression.
One difficulty with assessing and quantifying fluctuations is that inter-visit differences rely on data points
spread months apart in the average patient visiting glaucoma clinics. Using these snapshot IOPs to determine
whether fluctuations exist is unreasonable. Until there
are long-term IOP tracking devices, much of what is discussed in regard to IOP fluctuation is academic with little
practical application.
BACKGROUND: A NEED FOR BETTER DATA
As with many things in glaucoma, the effect of IOP
fluctuations and its implications is not at all straightforward. However, several major clinical trials have attempted to answer questions about the effects of fluctuations.
An analysis of patients enrolled in the Advanced
Figure 1. Autonomous IOP gauges, such as the one introduced by Sensimed, which functions as a strain gauge to
continuously measure IOP fluctuation over a 24-hour period,
will be crucial in better understanding the effects of pressure
fluctuation on developing glaucoma or disease progression.
Glaucoma Intervention Study (AGIS) suggested that IOP
fluctuation was predictive of worsening of visual fields,
but, interestingly, only among patients with low mean
IOP at the time of study enrollment.1 Patients enrolled
in the study who fell within the study’s upper tercile
of mean IOP did not exhibit a statistically significant
increased risk of visual field worsening based on whether
there was inter-visit fluctuations in IOP. Based on about
7 years of follow up, the AGIS investigators found that
increasing age and greater IOP fluctuation increased the
odds of visual field progression; the latter persisted as
a risk factor among patients who both did and did not
undergo cataract extraction.2
At the opposite end of the spectrum, investigators in
the Early Manifest Glaucoma Treatment study3 and the
European Glaucoma Prevention Study (EGPS)4 found no
correlation between inter-visit IOP fluctuation and risk of
glaucoma progression. An analysis of patients enrolled in
the Diagnostic Innovations in Glaucoma Study (DIGS)5
found no correlation between IOP variability and risk of
developing glaucoma. An analysis of both the OHTS and
EGPS studies performed by researchers not affiliated with
either study suggested that variability in IOP after enrollment and randomization were more likely to develop
primary open-angle glaucoma.6
Published retrospective and population studies,7-9 as
well as studies using at-home monitoring performed by
patients, suggest a link between IOP fluctuation and risk
of glaucoma. However, the methodology of these studies and/or small number of enrollees limits the ability to
draw definitive conclusions from their findings.
The sum total of all these data is that the correlation
between IOP fluctuation and risk of progressing from
ocular hypertension or to worsen glaucoma is inconclusive. There may be several reasons why. First, patient
populations are not the same from study to study. Some
of these studies enrolled patients with early glaucoma
while others involved patients with later stages of the
disease. If the outcomes of the AGIS study are to be
believed, patients with lower IOP who experience fluctuations may be more prone to progression. Second, different instruments and methods were used to determine
IOP in the studies—and in some cases, the conclusions
rely on patients checking their pressure at home. A third
(and very important) point is that the definition of IOP
fluctuation is different from study to study. Some of these
studies looked at diurnal fluctuation while others looked
at long-term, inter-visit variation in IOP readings. Also
very important, some studies failed to take into account
the influence of added medications or laser/surgical intervention during the follow-up period and how this might
have influenced the amplitude of IOP fluctuation.
TOWARD BETTER DATA
Twenty-four-hour IOP sleep studies have been proposed as a way to better understand IOP fluctuation.
However, one issue with sleep studies is that once
patients are placed in the very controlled environment of
the study, the applicability of the findings to real-world
scenarios may be limited. In other words, patients are
likely not going through their normal daily routines that
may include exercise, climbing stairs, running from meeting to meeting, or drinking coffee, and, therefore, we cannot extrapolate directly from the artificial environment
of a well-controlled sleep lab.
What is needed to better understand the effects of
24-hour changes in IOP is a measuring device that would
be independent of both the patient and investigator in
measuring pressure throughout the day. Several companies are working on such a device. One proposed device
was introduced by Sensimed and utilizes a noninvasive
contact lens with a strain gauge (Figure 1). This device
What is needed to better understand the effects of 24-hour
changes in IOP is a measuring
device that would be independent
of both the patient and investigator in measuring pressure
throughout the day.
—Malik Y. Kahook, MD
measures architectural changes at the limbus that may
occur secondary to pressure changes; thus, it is not a
direct measure of IOP change, per se, but rather a gauge
of curvature change as a function of pressure fluctuation.
There are also a number of companies studying
implantable devices that are either coupled with an
intraocular lens or might be implanted inside the eye
or in the sclera. These devices are, for the most part, in
the preclinical phase or the early clinical phase of validation to see if they actually correlate with gold standard
pressure measurement, which is still Goldmann applanation—which is to say, we do not have a good understanding of how reliable their output will be.
BUT THEN WHAT?
The prospect of definitively measuring IOP fluctuations over a 24-hour period and how the data might correlate to developing glaucoma or disease progression is
interesting academically. But how will we apply the newfound data in a practical manner to help our patients?
There are a number of ongoing studies looking at different medication classes, laser, and the various surgeries that can be performed and how they might flatten
the IOP curve during the 24-hour period. Right now we
know that some medication classes might be more effective than others at controlling night-time pressure: prostaglandin analogs work well at night, relatively speaking,
whereas β-blockers appear to not work very well at
night.10 We know that laser trabeculoplasty appears to
flatten the diurnal/nocturnal curve, but we do not know
much about surgical interventions such as trabeculectomy and glaucoma drainage devices and what they
actually do for pressure over a 24-hour period.11
I anticipate that sometime in the next 5 years we will
have reliable devices for measuring 24-hour IOP fluctuations. With that, we should see an explosion in research to
tease out whether fluctuations matter, and if so, how best
to flatten the diurnal/nocturnal curve. However, for now
and into the immediate future, there are simply too many
unanswered questions about the role of IOP fluctuation
in the development or progression of glaucoma for us to
substantially change our current clinical practices. n
Malik Y. Kahook, MD, is the Slater family endowed chair in ophthalmology; vice
chair, clinical and translational research;
and director, Glaucoma Service and
Glaucoma Fellowship, for the Department of
Ophthalmology at the University of Colorado School of
Medicine in Denver. He is a consultant to Alcon and holds
intellectual property interests in Abbott Medical Optics,
ClarVista Medical, Glaukos, Mile High Ophthalmics, New
World Medical, ShapeOphthalmics, and ShapeTech. Dr.
Kahook may be reached at (720) 848-2020; [email protected].
(Realini continued from page 8)
that contain β-blockers—lower IOP les effectively than in
patients not using oral β-blockers.6
Thus, for patients with contraindications to β-blocker therapy or those on systemic β-blockers, a fixed-combination that
does not contain a β-blocker might be a reasonable choice.
CONCLUSION
Fixed-combination agents provide a reasonable choice for
adjunctive therapy in patients requiring additional IOP lowering. In clinical practice, fixed-combinations may improve
therapeutic compliance and offer additional advantages.
However, they also have limitations, including the inability
to titrate dosages of the individual components. When
selecting a fixed-combination product, attributes of both
the patient and the drug should be considered in order to
optimize the efficacy and safety of the medical regimen. n
1. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for visual field progression at low intraocular
pressures in the advanced glaucoma intervention study. Ophthalmology. 2008;115(7):1123-1129.e3.
2. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al; Advanced Glaucoma Intervention Study. Predictive factors
for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111(9):1627-1635.
3. Bengtsson B, Leske MC, Hyman L, et al. Early Manifest Trial Group. Fluctuation of intraocular pressure and
glaucoma progression in the Early Manifest Glaucoma Trial. Ophthalmology.2007;114:205-209.
4. Miglior S, Torri V, Zeyen T, et al; EGPS Group. Intercurrent factors associated with the development of openangle
glaucoma in the European Glaucoma Prevention Study. Am J Ophthalmol. 2007;144:266-275.
5. Medeiros FA, Weinreb RN, Zangwill LM, et al. Long-term intraocular pressure fluctuations and risk of conversion
from ocular hypertension to glaucoma. Ophthalmology. 2008;115(6):934-940.
6. Gao F1, Miller JP, Miglior S, et al. The effect of changes in intraocular pressure on the risk of primary
open-angle glaucoma in patients with ocular hypertension: an application of latent class analysis. BMC Med Res
Methodol. 2012;12:151.
7. Werner EB, Drance SM, Schulzer M. Trabeculectomy and the progression of glaucomatous visual fields. Arch
Ophthalmol. 1977;95:1374-1377.
8. Oliver JE, Hattenhauer MG, Herman D, et al. Blindness and glaucoma: a comparison of patients progressing to
blindness from glaucoma with patients maintaining vision. Am J Ophthalmol.2002;133:764-772.
9. Rao HL, Addepalli UK, Jonnadula GB, et al. Relationship between intraocular pressure and rate of visual field
progression in treated glaucoma. J Glaucoma. 2013;22(9):719-724.
10. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on
intraocular pressure. Am J Ophthalmol. 2004;138(3):389-395.
11. Lee AC, Mosaed S, Weinreb RN, et al. Effect of laser trabeculoplasty on nocturnal intraocular pressure in medically treated glaucoma patients. Ophthalmology. 2007;114(4):666-670.
Tony Realini, MD, MPH, is an associate
professor of ophthalmology at West Virginia
University Eye Institute in Morgantown. Dr.
Realini reports financial relationships with
Alcon, Alimera; Lumenis (Speakers Bureau);
Optovue (Research Equipment); Reichert (Consulting); and
Topcon. Dr. Realini may be reached at (304) 598-6926;
[email protected].
1. Tsai JC, McClure CA, Ramos SE, et al. Compliance barriers in glaucoma: a systematic classification. J Glaucoma.
2003;12(5):393-398.
2. Sleath B, Robin AL, Covert D, et al. Patient-reported behavior and problems in using glaucoma medications.
Ophthalmology. 2006;113(3):431-436.
3. Robin AL, Novack GD, Covert DW, et al. Adherence in glaucoma: objective measurements of once-daily and
adjunctive medication use. Am J Ophthalmol. 2007;144(4):533-540.
4. Khouri AS, Realini T, Fechtner RD. Use of fixed-dose combination drugs for the treatment of glaucoma. Drugs
Aging. 2007;24(12):1007-1016.
5. Robin AL, Novack GD, Covert DW, et al. Adherence in glaucoma: objective measurements of once-daily and
adjunctive medication use. Am J Ophthalmol. 2007;144(4):533-540.
6. Schuman JS. Effects of systemic beta-blocker therapy on the efficacy and safety of topical brimonidine and
timolol. Brimonidine Study Groups 1 and 2. Ophthalmology. 2000;107(6):1171-1177.
The Knowns and Unknowns of
Generic Medications
Are the unknowns about generic medications enough to give us pause in using them for
routine therapy?
BY NATHAN M. RADCLIFFE, MD
I
n 2015, doctors and glaucoma patients are navigating
a pharmaceutical market that is becoming increasingly
focused on generic medications. However, physicians
and patients—in fact, market consumers—do not have
as much information on generic medications as we
would like, because a big part of what makes generic
medications inexpensive is the fact that the companies
manufacturing the medications do not typically perform
human clinical trials with those medications. Therefore,
doctors and patients are left to make treatment decisions
regarding generic medications in a way that balances
costs, patient safety, and efficacy. Yet, generic medications
are not always as cheap as one might expect. A recent
analysis by the Wall Street Journal noted that generic drug
costs are in fact “skyrocketing,” with some medications
costing 17,000% more than they had in the past.1
Further complicating the matter is that payer formularies shift frequently. For example, generic fixed combination medications may be placed on a third tier or higher
while branded fixed combinations or prostaglandin analogs may have better positioning. Additionally, some of
the more recently available generic prostaglandin analogs
(eg, travoprost 0.004% and bimatoprost 0.03%) may not
be listed on formularies or may not be available at some
pharmacies. Thus, it is often unclear which generic alternatives are truly available and how they will be priced.
When considering generics versus brand-name medications, we can categorize the issues into known and
unknown factors.
WHAT WE KNOW
We know that in the late 1990s, problems with the
formulations of generic nonsteroidal anti-inflammatory
drugs (NSAID) caused problems.2 Generic diclofenac was
implicated in almost 200 cases of corneal melting and
was eventually recalled. This case continues to serve as a
cautionary tale that unexpected problems can arise from
generic formulations.
According to standards from the US Food and Drug
Administration (FDA), generic medications must be formulated similarly to the innovator (branded) product,
and the concentrations of active ingredients must fall
within 10% of the innovator product. But several recent
studies demonstrate that important differences can
still exist. Kahook and colleagues3 studied the ability of
generic dorzolamide-timolol and latanoprost to withstand thermal challenges compared to the brand-name
counterpart. The study demonstrated that some formulations of generic latanoprost did not contain the required
amount of the drug, falling more than 10% below the
recommended levels. After a thermal stress, bottles of
generic latanoprost fell even further below the benchmark, whereas the branded product demonstrated superior stability. Finally, several bottles of generic medications
had higher levels of particulate matter than the brand
name medication.
Similarly, a study by Canadian researchers found that
generic medications differed from their brand name
counterparts in terms of bottle volume, viscosity, surface
tension, and bottle tip.4 The important point here is that
a generic bottle that has more or fewer drops might technically meet FDA requirements for bioequivalence, but in
the hands of the patient, the medication could run out
sooner, could deliver less medication, could waste more
drops, or might be more prone to spillage. These differences could leave patients without their eye drops, which
could lead to vision loss.
In several cases, the generic formulations of pressurelowering molecules have been replaced by alternative formulations that have demonstrated a better safety profile,
such as a lower risk of allergy or hyperemia. For example,
generic brimonidine 0.2%, generic bimatoprost 0.03%,
and travoprost 0.004% with benzalkonium chloride have
been discontinued by the innovator companies in favor
of alternate formulations that were felt to provide better safety profiles or that were more suitable to patients’
needs. Thus, in some cases, generic alternatives that are
suggested by the pharmacist or the insurance plan will
not have the same safety or efficacy profile. For example,
Myers and colleagues5 were able to demonstrate that
patients who were switched from generic latanoprost to
branded Lumigan 0.01% (Allergan) achieved a significant
intraocular pressure reduction. The amount of pressure
reduction achieved from the switch was roughly 4 mmHg,
which is also the amount of pressure reduction one might
expect from adding a second medication to latanoprost.
This is concerning, because generic latanoprost is often
suggested as a formulary alternative to latanoprost.
WHAT WE DO NOT KNOW
There are some issues regarding generic medications
that have been identified as potential issues, but there is
not yet enough information in the public sphere for us
to ultimately decide. Cost is a great example of this. It is
generally assumed that generic medications will be less
expensive; however this is not only the case always the
case, and the clinician is not able to tell in which circumstances savings will be large, small, or negligible. Without
this information, it is impossible to balance the risks and
benefits of a generic versus branded medication.
Another known issue that has unknown implications
is the value of the brand itself. In our society, we tend
to be enamored with brand name products. We want
to wear brand name jeans, drink brand name soda, and
populate brand name restaurants, and that is because we
know what we are getting. In a marketplace driven by the
principle of caveat emptor, predictability and reliability
are important factors for consumers. It is likely that these
same principles apply to the medications we put in our
bodies. I think patients feel safer knowing that a drug has
a track record of safety and efficacy. They prefer to know
that the drugs we are prescribing have been studied in
well-controlled clinical trials, because that supplies assurance of predictability and reliability.
It is known that patients have difficulty taking their
medications—and confusion about which medication to
take and when to take it is part of the problem. Part of
the inherent value of a brand is the ability to recognize
the product and to know its manufacturer and packaging
is consistent over time. For example, it is implicitly the
case that Cosopt (Merck) is an easier name to recognize
then dorzolamide hydrochloride 2% timolol maleate 0.5%
solution. In my clinical experience, the long title of the
generic medication often leads patients to misreport the
medication they are taking to their internist, often leaving off one of the two medications contained in the fixed
combination product. This can result in the incorrect
medication being refilled, and it also creates confusion,
even with trained ophthalmic technicians. How much of
a problem is caused by confusion regarding the names of
generic medications, however, remains unknown.
Another unknown is how much disruption of care
is caused each year when prescription plan formularies arbitrarily change the tiers of branded medications,
forcing clinicians to change a patient’s medication and
disrupting their routine care. Although a change may save
dollars paid out at the pharmacy, do increased office visits
caused by these changes cancel out those costs?
Because patients may get confused about their medications, I believe the practice of starting a patient off on a
generic medication and moving him or her to a brand if
the first line generic is not effective is a suboptimal one,
because this strategy may confuse the patient by exposing him or her to several medicines. I recall a patient who
was briefly treated on dorzolamide 5 years earlier who
only seemed to remember the bottle with “the orange
cap.” For many patients, care is best streamlined if we can
keep them on one medicine during their whole career as a
patient. To do that, you want to pick the best one to start
with; if that is a brand medicine, you would ideally like to
start with that, because switching medicines and formulations—especially if there are different dosing requirements
or instructions—causes confusion that interferes with
compliance and that might hurt outcomes.
CONCLUSIONS
When I am starting a patient on topical therapy, I tell
him or her that I want to pick the best medication for
their particular needs, but that I need a little help. The
patient will often do a good job of explaining what is on
his or her mind. Some will let me know they are under
financial duress, while others will tell me that they want
me to use the medicine that I think is the best. I will
never force a patient to use a medicine that will cause
financial stress, but if the patient asks for the medicine I
have the most confidence in, I will suggest a brand medicine—because not only do I have my clinical experience
to rely on, but there is a lot more literature on branded
medicines confirming their safety and efficacy in treating
glaucoma. Furthermore, the potential to offer samples or
enroll patients in assistance programs gives them a path
to affording the medicines I believe they need to stave off
vision loss from glaucoma. n
Nathan M. Radcliffe, MD, is an assistant
professor of ophthalmology and director of the
glaucoma service at New York University in New
York. He has served on the speakers’ bureaus of
Allergan and Alcon Laboratories. Dr. Radcliffe
may be reached at (212)263-2573; [email protected].
1. Silverman E. How Much? Some Generic Drug Prices Are Skyrocketing: Analysis. Wall Street Journal. http://blogs.
wsj.com/pharmalot/2014/08/14/how-much-some-generic-drug-prices-are-skyrocketing-analysis/. Aug. 14, 2014.
Accessed July 22, 2015.
2. Flach A. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Tr Am Ophth
Soc. 2001;99:205-212.
3. Kahook MY, Fechtner RD, Katz LJ, et al. A comparison of active ingredients and preservatives between brand name
and generic topical glaucoma medications using liquid chromatography-tandem mass spectrometry. Curr Eye Res.
2012;37(2):101-108.
4. Mammo ZN, Flanagan JG, James DF, Trope GE. Generic versus brand-name North American topical glaucoma drops.
Can J Ophthalmol. 2012;47(1):55-61.
5. Myers JS, Vold S, Zaman F, et al. Bimatoprost 0.01% or 0.03% in patients with glaucoma or ocular hypertension previously treated with latanoprost: two randomized 12-week trials. Clin Ophthalmol. 2014;8:643-652.
Side Effect Profiles of
Glaucoma Drug Classes
Because of the various classes of medications available for use, it is often possible to switch
patients off of drugs they may not be able to tolerate.
BY ROBERT J. NOECKER, MD, MBA
T
he agents used for treatment of glaucoma are generally safe and well tolerated, although there are
some side effects that glaucoma specialist should
be aware of in order to have a proper informed conversation with patients. This article reviews some of the
more common side effects associated with the various
classes of medications used for treating glaucoma.
PROSTAGLANDIN ANALOGUES
Prostaglandin analogues (PGAs) are systemically very
safe and they are highly effective as a front line medication
for controlling elevated IOP. The ocular side effects associated with PGAs are the ones we are most often concerned
about. By and large, side effects of PGAs are not medically
dangerous or vision threatening; in most cases, patients may
be able to tolerate the side effect to gain the benefit of the
medication. However, because most of the side effects of
PGAs have cosmetic sequelae, and they may limit their utility as a single eye drug, insofar as the cosmesis will be that
much more apparent if only one eye is affected.
In particular, hyperemia (Figure 1) is the most common side effect associated with PGAs and it most
commonly occurs after instillation of the first dose. A
patient’s response to hyperemia is variable and hard to
predict, although the condition is usually self-limiting
and reversible.
Another side effect commonly associated with PGAs
is periocular changes, which can vary in degree from
reddening of the skin around the eye to increased pigmentation (darkening of the skin around the eye) in
some patients (Figure 2). These tend to be related to
getting the drug on the skin, so washing the drug off
may alleviate it.
PGAs may cause an increase in fat atrophy around the
eye, and so there may be a more sunken appearance to
the eye—again, most likely due to excessive eye drop
instillation and drug getting on the area around the eye.
Patients with less fat around their eyes tend to have a
more dramatic response. The condition is reversible if
PGAs are stopped.
Figure 1. Hyperemia, as seen in this patient, is the most common side effect associated with PGAs.
Figure 2. PGAs can cause reddening of the skin around the
eye as seen in this patient.
One condition that may not be reversible is iris pigmentation, which although associated with all of the PGAs
in the class, has been reported most frequently associated
with latanoprost. Patients with hazel eyes are at highest
risk, as an increase in melanosomes (which causes darkening of the iris appearance) will rarely be detectable in
darker eyes. Patients with blue eyes are at lesser risk for iris
pigmentation. Although not vision threatening, patients
who are concerned about their hazel eye color should be
advised of the risk of iris darkening.
PGAs have been associated with prolongation of
inflammation. They do not cause inflammation de novo,
but patients with inflammation, such as iritis or uveitis,
can experience increased inflammation. Around the
time of cataract surgery, there can be an increase in cell
or flare postoperatively, which is treatable, but there is a
risk of developing cystoid macular edema. As such, PGAs
may not be vision threatening, but their use around the
time of cataract surgery can be additive in the risk of
developing cystoid macular edema, which can be vision
threatening if not detected and adequately addressed.
Another common issue with PGAs is eyelash growth,
although this may be a desired effect in some patients.
PGAs are used in some settings to intentionally spur eyelash growth; however, if the agent is used in only one eye,
it will obviously be more detectable.
PGA INTOLERANCE: NEXT STEPS
Patients may be moved off of PGAs for a variety of reasons,1-4 including lack of response to the initial therapy
and/or because of intolerance of the side effects. Among
patients in whom I started with a generic latanoprost
and there was not adequate response, I would consider
switching in the class to Lumigan (bimatoprost 0.01%,
Allergan) or Travatan Z (travoprost 0.04%, Alcon) to
get more efficacy. There are some patients who will not
respond to any PGAs while others are more selective in
their response. I believe it is worth the effort to attempt
a switch before abandoning the class so that patients can
stay on one bottle of therapy if possible.
My next level of intervention for patients after PGAs is
to consider selective laser trabeculoplasty or to add additional medical therapy—either a single agent (α-agonist,
carbonic anhydrase inhibitor [CAI], or β-blocker) or a
fixed-combination agent. My experience has been that
if a single agent (ie, the PGA) did not lower the pressure
adequately, then the stakes have been raised and there
is a need to get the pressure under control as quickly as
possible. And so, I tend to add fixed-combination agents
as adjunctive therapy, both for efficacy reasons, but also to
simplify therapy and reduce exposure to multiple drops.
ADJUNCTIVE AGENT CLASSES
There are some known side effects with the classes
of medications used for adjunctive therapy that are
worth noting.
α-Agonist
Patients taking α-agonists, such as brimonidine, may
develop an allergy to the medication over time. The
active ingredient becomes oxidized, and patients begin
to mount a local hypersensitivity and conjunctivitis. This
tends to be dose-related and so does not typically occur
after the first dose.
This class has also been associated with pupil changes in
some patients; dry mouth (especially at high doses) if the
drug becomes systemically absorbed and gets to back of
throat; and changes in blood pressure (a rare side effect).
CAIs
CAIs are systemically safe, but dorzolamide 2% is acidic
preparation and so it can cause some discomfort upon
instillation. It can be affect the cornea and cause ocular
surface changes. Brinzolamide (Azopt, Alcon) is a suspension, so blurred vision may occur, and a metallic taste in
the mouth has also been reported by some patients.
β-Blocker
β-blockers have a fairly long list of known systemic
effects, but they are well tolerated by the eye. The biggest concern with this class relates to respiratory and
cardiac issues, namely bronchospasm, exacerbation of
asthma, bradycardia, and exercise intolerance. There are
also a number of infrequently occurring but potentially
noteworthy side effects such as depression, decreased
libido, and exacerbation of pre-existing heart problems.
CONCLUSION
The brand medications we use for treating glaucoma
have all undergone rigorous testing to prove their safety
and efficacy. Although generic medications are not subject to equivocal testing, they contain the same active
ingredients as their brand comparators and, therefore,
should not introduce any new side effects (although
there is suggestion that certain generic formulation
may be associated with higher rates of some side effects
compared with their brand comparators). Nevertheless,
because of the multiple classes of medication available
for use, it is often possible to switch patients to other
medications if they have a problem with tolerance. Laser
trabeculoplasty remains a viable option for patients
intolerant of medical therapy before the need for interventional surgery is entertained. n
Robert J. Noecker, MD, MBA, practices at
Ophthalmic Consultants of Connecticut in
Fairfield and is an assistant clinical professor at
Yale. He is a consultant to Alcon and Allergan.
Dr. Noecker may be reached at
(203) 366-8000;[email protected].
1. Agange N, Mosaed S. Prostaglandin-induced cystoid macular edema following routine cataract extraction. J
Ophthalmol. 2010;2010:690-707.
2. Panteleontidis V, Detorakis ET, Pallikaris IG, Tsilimbaris MK. Latanoprost-Dependent Cystoid Macular Edema
Following Uncomplicated Cataract Surgery in Pseudoexfoliative Eyes. Ophthalmic Surg Lasers Imaging. 2010;9:1-5.
3. Yeh PC, Ramanathan S. Latanoprost and clinically significant cystoid macular edema after uneventful phacoemulsification with intraocular lens implantation. J Cataract Refract Surg. 2002;28(10):1814-1818.
4. Moroi SE, Gottfredsdottir MS, Schteingart MT, Elner SG, et al. Cystoid macular edema associated with
latanoprost therapy in a case series of patients with glaucoma and ocular hypertension. Ophthalmology.
1999;106(5):1024-1029.
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